Istinye University, Faculty of Medicine, Department of Clinical Sciences, Department of Pharmacology and Clinical Pharmacology
"HIV/AIDS: One of the greatest tragedies of the 20th century. Is it still?"
Introduction
Following in the early 1980s as the HIV/AIDS cases began to appear in the US, and its recognition by the Centers for Disease Control and Prevention in the US, intensive studies were carried out, and the causative virus (Human Immunodeficiency Virus (HIV)), and AIDS (Acquired Immunodeficiency Syndrome), which develops in people infected with this virus after a severe decrease in the effectiveness of the immune system were defined. The fact that more than forty years have passed since the first recognition of HIV/AIDS and that more than 40 millions of people worldwide have lost their lives as a result of HIV and AIDS the disease caused by this virus and its complications, and that it still causes the death of a large number of people worldwide unfortunately requires a "Yes" answer to the question given in the title above for this virus and this disease that is caused by it.
After the first recognition mentioned above in the early 1980s, intensive studies have been and are still being carried out in the scientific field to identify HIV (the virus), to search for effective drugs against it and to bring these drugs into the treatment. In 1987, after the discovery of the first antiretroviral drug zidovudine (AZT), and especially since the mid-1990s, the development of effective drugs (antiretroviral drugs) against HIV and their introduction to the treatment, especially in HIV-infected people who can access these drugs and use these drugs regularly without interruption, the replication of the virus can be controlled. Although they provide suppression and prevent the transmission of the virus (e.g. to spouses or partners, and from mother to fetus during pregnancy), and has achieved a great success in preventing the development of AIDS and the complications associated with this disease, which develops in the progressive period due to this virus and results in death if left untreated, it is essential for the patient to use his/her medications regularly as prescribed by his/her physician in order to keep HIV in his/her body under control. However, over the past forty years, unfortunately, no drug or drug combination that can completely eradicate HIV (completely eliminate the virus in the body), i.e. a complete cure for HIV or no vaccine for HIV prevention has been found and brought into medical use. So for people with HIV to avoid infecting others with the virus, and in order not to lose their lives due to AIDS and AIDS-related complications that develop due to the progression of HIV infection, they need to use the antiretroviral drug treatment prescribed to them by specialised physicians for the rest of their lives. And with this treatment regimen, HIV will continue as a "chronic disease" that will be present but suppressed for the rest of their lives. Therefore, although with regular treatment of antiretroviral drugs the multiplication of HIV in the body following HIV infection is suppressed, and transmission to other people and development of AIDS is prevented, the best way to prevent from HIV/AIDS is "a good education, awareness and prevention of transmission and protection from transmission". In this context, since one of the most common ways of HIV transmission is sexually, it is of great importance that especially people who are sexually active and have sex with different people to use effective sexual protection methods including condoms correctly and regularly.
History
The first known identification of HIV/AIDS was made in the early 1980s with cases reported to the Centres for Disease Control and Prevention in the United States. In the summer of 1981, young homosexual men started to get sick and die from opportunistic infections that their bodies could defend with their immune systems. It was reported that the bodies of the infected people were becoming very weak and dark pink coloured spots developed on their skin, especially on the arms and face due to Kaposi's sarcoma, which is a very rare and aggressive form of cancer. This deadly disease was even named as "gay plague" for a while, as it was particularly prevalent in the big cities of the U.S. such as New York and San Francisco and among homosexual men. And unfortunately, these patients rapidly deteriorated and lost their lives due to the development of another opportunistic infection following an opportunistic infection that was tried to be treated despite all efforts of their doctors.
So, how did the "virus" HIV, the causative agent of this disease, which was later discovered, emerge and how was it transmitted to the society? HIV (Human Immunodeficiency Virus), a retrovirus, whose origins have been investigated for many years and whose two types, HIV-1 and HIV-2, have been identified, is believed to have originated in mid-west Africa (Congo Basin) from Simian Immunodeficiency Virus which causes immunodeficiency of primates. It has been reported that it has been transmitted from primates to humans as a result of interspecies transmission since the early mid-1900s and spread from the African continent to other continents and to the world through genetic mutations, intercontinental migration, unprotected sexuality, i.v. drug use with the same syringe, etc.
Today, since the early 1980s, when HIV/AIDS was first recognized, to the present day, the disease has caused and continues to cause more than 40 million deaths worldwide. In 2022, 1.3 million new HIV cases have been identified, 39 million people worldwide are infected with HIV virus as of 2022 and the number of AIDS-related deaths due to this virus in 2022 was 630,000. Of the 39 million people infected with HIV (living with HIV), 20.8 million live in East and Southern Africa and 4.8 million live in West and Central Africa. According to a study published in 2023, in Turkey, the cumulative number of HIV infections as of the end of November 2020 was 27767 and the number of newly diagnosed cases in 2020 was 4037. It was stated that there has been a 400 per cent increase in the number of HIV-infected people in Turkey from the beginning of the 2000s until 2018, and as of the end of 2021, according to the official records of the Ministry of Health of Turkish Republic, in Turkey 32 thousand people are HIV-positive and 26 thousand of them are men.
Characteristics and mechanism of action of "HIV"
So how does HIV show its effects in the body and cause failure in the human immune system and subsequently AIDS disease and the death of people with complications related to this disease? HIV is a retrovirus; it changes the genome of the host cell by inserting a DNA (deoxyribonucleic acid) copy of its RNA (ribonucleic acid) genome (genetic material) into the DNA of the host cell it invades. HIV "infects immune system cells" of the host, mainly CD4+ T cells, macrophages and dentritic cells. HIV destroys CD4+ T cells.
How HIV infects cells in the body can be summarised as follows; the surface glycoprotein "gp120" of the mature HIV particle binds to the "CD4" receptor on the host cell. All CD4-positive (CD4+) cells such as helper T cells, macrophages and dentritic cells and astrocytes, which are important structures of the human immune system, are sensitive to HIV. After HIV's gp120 binds to CD4 in the host cell, gp120 binds to co-receptors such as chemokine receptor 4 and chemokine receptor 5 (structures involved in various signal transduction in the body) and as a result, structural changes in gp120 and viral RNA cause the formation of proviral DNA with various enzymes in the host cell and enter the human cell nucleus and these processes complete the transmission of HIV to the host cell and the formation of a permanent infection.
After integration into the host cell genome, the first viral particles can be detected after approximately 6 hours, i.e., approximately 24 hours after infection, the first produced viruses are released from the infected cell. Because antibodies (defense structures produced by immune cells) that detect antigens (foreign structures entering the body that cause undesirable situations e.g. infections etc.) after mutations are also infected and the infected helper T cells (helper T lymphocytes) are eliminated by the immune system, and because of HIV-specific proteins such as Nef and Tat prevent the maturation and replacement of new immune system cells, the level of helper T cells constantly decreases and the immune system cannot perform its normal functions. In the infection of long-lived cells such as macrophages, astrocytes and memory T cells, a latent period lasting for years (dormancy phase, latent phase) occurs, and the production of infectious HIV particles occurs with the activation of these cells. In conclusion; HIV's inadequacy in the immune system causes the development of opportunistic infections and cancers in HIV-infected people.
HIV tests
HIV can be detected by laboratory tests and the infection can be staged according to various signs and symptoms. One of the most important strategies to reduce the burden of HIV worldwide is to increase the rate of HIV testing. It is stated that 1.2 million people in the US live with HIV and 14% of them are unaware of this situation despite the applicability and accessibility of HIV tests. In many regions of the world, it is reported that one third of HIV carriers discover that they are infected in the advanced stage of AIDS or immune deficiency. This situation shows how important it is to perform HIV test in order to detect HIV and then to keep its spread under control.
Antigen-specific antibody (a kind of immune defence products formed in the body against the antigen) formation (seroconversion) in HIV-infected individuals may occur 3 to 12 weeks after the first infection. The primary diagnosis before antibody formation can be made by measuring HIV-RNA or p24 antigen.
HIV tests used to diagnose HIV infection are mainly of three types: (1) antibody tests, (2) antigen/antibody tests, (3) nucleic acid tests (NATs).
Antibody tests are tests that detect antibodies produced by the body against HIV in blood and oral fluid. Most rapid tests and home tests are antibody tests.
Antigen/Antibody tests are tests that can detect both HIV antigen and antibody in the blood. Antibody and antigen/antibody tests are routine tests used initially. NATs are tests that look for HIV in the blood. NATs are expensive tests and are not used routinely, but are used if a person has high-risk exposure to HIV or has early symptoms of HIV with possible exposure. Following a positive HIV test result, a follow-up test is required to confirm the diagnosis. If the follow-up test is also positive, the person is diagnosed as HIV positive.
There may be a possibility of false negative results in HIV tests, this should be evaluated depending on the window period before the antigen or antibody is positive. A viral RNA load test can be performed from a very early infection (less than 2 weeks) and the person can be retested with a repeat serial test after 1 month or 3 months. In some patients, a positive test may not be obtained for up to 3 months, so an explanation of the window period and an appointment for further testing is given for each negative test. If more than 3 months have passed since the at-risk behaviour and the test result is negative, the test is read as true negative.
HIV infection
Classifications of HIV infection
According to the World Health Organisation (WHO) for adults and adolescents over 15 years of age:
Clinical stage 1
HIV infection is asymptomatic (no symptoms) and may include generalized lymph node enlargement.
Clinical stage 2
(mildly symptomatic stage) Various clinical manifestations of early HIV infection; weight loss of less than 10%, persistent respiratory infections (e.g. sinusitis, bronchitis, pharyngitis), various skin diseases (e.g. flares of Herpes zoster, periles (Candida infections, a type of fungus on the rim of the mouth and lips), recurrent mouth ulcers, papular itchy skin rashes, seborrhoeic dermatitis, fungal nail infections).
Clinical stage 3
(intermediate symptomatic stage) As the disease progresses, additional symptoms appear; weight loss of more than 10%, prolonged (more than 1 month) unexplained diarrhoea, bacterial infections such as pulmonary tuberculosis, pneumonia, pyelonephritis, meningitis, septicaemia, bone and joint infections. Mucocutaneous infections such as recurrent oral aphthae, acute necrotising ulcerative stomatitis, gingivitis and periodontitis may also occur during this phase.
Clinical stage 4
(severe symptomatic stage) includes all AIDS-defining illnesses. These include HIV wasting syndrome, Pneumocystis (jirovecii) pneumonia, recurrent severe bacterial pneumonia, extrapulmonary organ tuberculosis, HIV encephalopathy, central nervous system toxoplasmosis, oesophageal candidiasis and Kaposi's sarcoma. This stage also includes cytomegalovirus (CMV) infections (such as retinitis (in the eye) or other organ infections), various severe fungal infections (e.g. extrapulmonary organ cryptococcosis, disseminated mycoses (e.g. coccidiomycosis, coccidiomycosis e.g. coccidiomycosis, extrapulmonary histoplasmosis, tracheal, bronchial or pulmonary candida infection, extrapulmonary organ cryptococcosis including meningitis), various severe parasitic, bacterial and viral infections (e.g. isosporiasis, disseminated nontuberculous mycobacteria infection, visceral herpes simplex infection), acquired HIV-associated rectal fistula (canal-shaped structures forming in the anus), various cancers (e.g; cerebral or B-cell non-Hodgkin's lymphoma), a serious brain infection progressive multifocal leukoencephalopathy (PML), and HIV-associated cardiomyopathy (heart muscle disease leading to impaired heart function) or nephropathy (kidney damage). However, the presence of these conditions not accompanied by AIDS-defining illnesses should warrant confirmatory testing.
The WHO stages of HIV infection for children under 15 years of age (although stage 1 is similar) can be reviewed in the current WHO guidelines.
According to the CDC: For adults aged 6 years and older:
Stage 0: Time between a negative or indeterminate HIV test followed by a positive test less than 180 days later
Stage 1: CD4 count ≥ 500 cells/µl and no AIDS-defining conditions
Stage 2: CD4 count 200 to 500 cells/µl and no AIDS-defining conditions
Stage 3: CD4 count ≤ 200 cells/µl or AIDS-defining conditions
Unknown Insufficient information is available to make any of the above classifications.
There are three main stages of HIV infection; (1) Acute HIV Infection, (2) Chronic HIV Infection, (3) AIDS.
Acute HIV infection, which is the first period; In the first 2-4 weeks following HIV infection, flu-like symptoms such as fever, headache, redness, itching and rash are observed in the person. During this period, the virus rapidly multiplies and spreads throughout the body and destroys the CD4 cells (CD4 T lymphocytes) of the immune system by attacking them. In the acute phase, the level of HIV in the body and the risk of transmission of the virus are high. People in this phase can benefit greatly from antiretroviral therapy.
In the second phase (chronic HIV infection) HIV continues to replicate in the body at a slower rate, this phase is also called asymptomatic HIV infection or clinical latent phase. People with chronic HIV infection may not have HIV-related symptoms. In the absence of antiretroviral therapy, chronic HIV infection can progress to AIDS in 10 years or more, more rapidly in some people. If antiretroviral therapy is taken, a person can remain in this stage (chronic HIV infection stage) for decades. Although HIV transmission is still possible at this stage, people with an undetectable viral load cannot sexually transmit the virus to HIV-uninfected people if antiretroviral therapy is used completely and regularly as prescribed and if the treatment is continued.
AIDS is the most severe and the final stage of HIV infection. The HIV virus has severely damaged the immune system and the person is unable to fight against opportunistic infections. People with HIV are diagnosed with AIDS if their CD4 levels are below 200 cells/mm3 or if they have various opportunistic infections. People diagnosed with AIDS have a very high viral load and can easily infect other people with HIV. If left untreated, people with AIDS survive for approximately 3 years.
Transmission
HIV is transmitted through the infected person's blood and certain other body fluids, including semen, vaginal fluid, preseminal fluid, rectal fluid and breast milk. For HIV to be transmitted, these fluids containing the virus must enter the other person's bloodstream through a mucous membrane (rectum, vagina, penis or mouth), open cuts or wounds, or direct injection.
Main transmission routes of HIV
Sexually (anal or vaginal intercourse with a person who has HIV without using condoms or with a person who has HIV and is not using regularly medicines for HIV treatment or prevention) (The most common cause of new HIV infections worldwide is sexual intercourse. Having another sexually transmitted disease can increase the risk of getting or transmitting HIV).
Using the same needles, syringes or injecting drug equipment with people who has HIV.
Perinatal (from mother to her baby) transmission during pregnancy, childbirth or breastfeeding. Anti-HIV (antiretroviral) medication during pregnancy prevents HIV transmission to the baby, and in areas where baby formula and safe water are available, it is recommended that women with HIV do not breastfeed their babies.
In very rare cases, transmission by oral sex, biting, deep open-mouth kissing, pre-chewed food (e.g. giving it to children, known cases only by mixing blood from the mouth of the HIV-infected carer with food).
HIV can also be transmitted through blood or tissue or organ donation, but this is now rare due to the testing of the donor (the person who gives blood, tissue or organs) before blood, tissue and organ transplantation.
It has been reported that HIV is not transmitted by contact with saliva, tears or sweat, by shaking hands, hugging, sharing food utensils, swimming in the same pool, using the same toilet seat, being bitten by flies or other animals.
Treatment approaches
Antiretroviral drugs: Drugs used in the treatment and prophylaxis (prevention) of HIV/AIDS. In 1987, after the first antiretroviral drug, zidovudine (AZT), was introduced to treatment, antiretroviral drug research has accelerated especially since the mid-1990s and the number of antiretroviral drugs introduced into treatment has increased rapidly. With the use of antiretroviral drugs in the treatment of HIV-infected individuals and regular and uninterrupted treatment, the viral load (the amount of virus in individuals) of HIV-infected individuals has been reduced, the state of insufficiency caused by HIV on the immune system of individuals has been corrected, individuals have been able to continue their lives normally and HIV transmission to other individuals has been prevented.
Today, antiretroviral drugs are basically divided into six groups including nucleoside-nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), integrase inhibitors (INSTI), fusion inhibitors (FI) and chemokine coreceptor 5 antagonists. These drugs inhibit the proliferation of HIV at different stages of the life cycle of this virus in humans. Entry inhibitors such as fusion inhibitors and chemokine coreceptor 5 antagonists act by inhibiting the entry of the virus into the cell, NRTIs and NNRTIs inhibit the synthesis of proviral DNA, INSTIs inhibit the integration of viral DNA into genomic DNA and PIs inhibit the maturation of the virus. One of the fundamentals of antiretroviral treatment of HIV is "the administration of antiretroviral drugs in at least two, preferably three-drug combinations" to both inhibit (prevent) several steps in the life cycle of the virus in the human body and to prevent the virus from developing resistance to drug treatment. For this purpose, the most commonly used three-drug combination therapies is adding two NRTI, which are the mainstay of antiretroviral therapy, an NNRTI, PI or INSTI to 2 of the NRTIs (2 NRTI+1 NNRTI, 2NRTI+1 PI or 2NRTI+1INSTI). Unless there is a resistant HIV strain, treatment is started with 3 fully active drugs in this way. Today, there are drug regimens that contain triple drugs in the form of a single tablet.
Examples of the main antiretroviral drug groups are given below:
NRTIs: abacavir (ABC), zidovudine (AZT), emtristabine (FTC), tenofovir disoproxil (TDF), tenofovir alefenamide (TAF),
NNRTIs: efavirenz (EFV), etravirine (ETV), nevirapine (NVP), rilpivirine (RPV), doravirine (DOR)
PIs: lopinavir/ritonavir (LPV/r), darunavir/ritonavir (DRV/r), atazanavir/ritonavir (ATV/r)
Booster: ritonavir (RTV, r), cobistat (COBI, c)
INSTIs: raltegavir (RAL), elvitegravir/cobistat (EVG/c), dolutegravir (DTG), biktegavir (BIC)
Fusion Inhibitors (FI): enfuvirtide (ENF, T20)
Chemokine coreceptor 5 (CCR5) Antagonist: maraviroc (MVC)
HIV-1 Inhibitor after binding against CD4: ibalizumab
The best combination varies according to the patient: the most appropriate antiretroviral drug combination regimen is selected by the specialist physician by evaluating factors such as virological (on the virus) efficacy, toxicity, pill load, dose range, drug-drug and drug-food interactions, recent and previous drug resistance results, other comorbidities and cost. Before starting treatment, the patient should be carefully informed about the importance of regular drug use, drug-drug, drug-nutrient interactions and various side effects that may occur due to these drugs. In order for antiretroviral drugs to be effective and for HIV not to develop resistance against these drugs, the drugs should reach therapeutic levels in the blood, and for this purpose, these drugs should be used regularly without skipping or interruption and as prescribed by the physician.
Antiretroviral therapy can be used for HIV treatment as well as for pre-exposure and post-exposure prophylaxis (prevention). In post-exposure prophylaxis, it is recommended to start prophylactic antiretroviral therapy as soon as possible (≤72 hours (within 72 hours)) after risky contact with blood and body fluids, which should be managed by a physician. Within the scope of this preventive treatment, TDF(TAF)/FTC+RAL, TDF(TAF)/FTC+DRV/r, TDF(TAF)/FTC+DTG or TAF/FTC/BIC are used for one month. Pre-exposure prophylaxis (PrEP) is used to prevent HIV infection in people who do not regularly use condoms before risky contact (e.g. risky sexual contact). The person's eligibility for treatment is assessed and managed by a sexual health professional. The regimen is once daily TDF/FTC continuously. "On-demand" PrEP is administered with a double dose of TDF/FTC 2-24 hours before sexual intercourse, and one dose each 24 and 48 hours after the first dose, a total of 4 doses. PrEP is reported to be one of the most effective methods in preventing new HIV cases.
Antiretroviral drugs used in HIV treatment and prophylaxis have various "side effects", some of which may be serious. To summarise these; NRTIs may cause mitochondrial toxicity which may manifest as peripheral neuropathy (damage to peripheral nerves and loss of function), pancreatitis (inflammation of pancreas), lipoarthrophy (shape changes due to changes in subcutaneous fat tissue distribution) and hepatic steatosis (fatty liver), less frequently fatal lactic acidosis, rapid elevation of aminotransferase enzymes, hepatomegaly (liver enlargement), metabolic acidosis (acidosis with decreased bicarbonate and pH of the serum), lipoarthrophy and insulin resistance. NNRTIs may cause gastrointestinal intolerance (digestive system disorders) and skin rashes (rarely serious conditions such as Steven-Johnson syndrome). NNRTIs are metabolised by the CYP450 enzyme system, which is involved in the metabolism of many drugs in the body, and this causes them to interact with many drugs. This situation should be taken into consideration in the treatment with these drugs, drug interactions, dose adjustments of these drugs, and some combinations should not be should be taken into consideration by the physician. PIs can cause gastrointestinal intolerance (digestive system disorders), metabolic (hyperglycemia (increased blood glucose levels), hyperlipidemia (increased blood lipid levels)) and lipodystrophy (disorders of adipose tissue in the body) including morphological irregularities (lipoarthrophy (disorders of fat tissue distribution in the body). PIs may also cause redistribution syndrome and body fat accumulation central obesity, dorsocervical (in the neck and back) fat accumulation (buffalo hump), peripheral and facial thinning, breast enlargement, appearance smiliar to Cushing’s syndrome, cardiac conduction disorders including PR and QT interval prolongation, drug-induced hepatitis and rarely severe hepatotoxicity (liver toxicity). It is being investigated whether PIs are also associated with bone loss and osteoporosis with long-term use. Similar to NNTIs, PI inhibitors are metabolised by the CYP450 enzyme system and may cause a wide range of drug interactions by interacting with this enzyme system. The chemokine coreceptor 5 antagonist maraviroc may cause upper respiratory tract infection, cough, fever, rash, dizziness, muscle and joint pain, diarrhoea, sleep disturbance, elevated serum transaminases, hepatotoxicity that may precede a systemic allergic reaction, myocardial ischemia (reduced blood supply to the heart muscle) and infarction. May cause hypotension (decrease of blood pressure) in severe renal failure. Maraviroc is metabolised by the CYP3A4 enzyme and is a substrate (substances on which an enzyme or other structures act) of pgp (pgp; a protein that pumps out foreign substances in the body), for this reason, drug interactions should be considered. Although INSTIs are relatively well tolerated, headache and gastrointestinal (digestive system) adverse effects are the most commonly reported adverse effects, combinations with other antiretroviral drugs should be considered in terms of additional adverse effects and/or drug interactions. In the light of available data, effects on lipid (fat) metabolism are more favourable than PI and efavirenz. Rare serious side effects of INSTIs are hypersensitivity reactions and rhabdomyolysis (destruction of skeletal muscles).
In conclusion, although HIV, and AIDS, which is a fatal disease caused by this virus, have been defined and known for more than forty years, it still affects the lives of millions of people around the world and still causes hundreds of thousands of deaths every year. However, the transmission and spread of this disease can be kept under control by raising awareness about HIV/AIDS, especially through education, and as a result of this, the correct and regular use of effective protected sex methods such as condoms especially by sexually active people who have sex with different people, and not using contaminated needles and not sharing them.
There is still no complete cure for HIV and no vaccine against HIV. Existing “antiretroviral treatments” can be used before and after exposure for HIV prophylaxis, as well as being used effectively for treatment in HIV-infected people. However, eventhough they reduce the viral load in a person with HIV over a period of time with regular use and reduce it to undetectable levels and prevent transmission to people who do not have HIV, they cannot completely destroy the virus in the person with HIV, and if medication use is stopped or the routine is disrupted, HIV can continue to multiply in the body of a person with HIV in a resistant form. And after a certain period of time, after the progressive infection turns into AIDS, the person dies. With lifelong regular use of medication, the person continues his/her normal life like a person with a chronic disease and does not transmit HIV to other people.
"Protection" from this infectious disease, which is fatal in the absence of effective treatment, is the most effective method not only in terms of preventing the spread, but also in terms of the fact that access to antiretroviral treatment is not always easy worldwide in case of infection, and in case of access, difficulties in treatment, side effects and drug interactions can be encountered. It is useful to emphasize once again the importance of social and international education and awareness on HIV/AIDS and the application of effective prevention methods, considering that being protected (not transmitted) is a better situation because HIV cannot be completely eradicated (completely destroyed from the body) and these drugs need to be used for life.
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